Human cancers are sustained in their growth by a pathological counterpart of normal adult stem cells, cancer stem cells. This concept was first described in human myeloid leukemias and has later been extended to solid tumors such as breast and brain cancer. A quantitative understanding of cancer stem cells requires a mathematical framework to describe the dynamics of cancer initiation and progression, the response to treatment, and the evolution of resistance. In this proposal, we suggest to use mathematical and experimental techniques to investigate the biology of cancer stem cells. We will derive mathematical models to investigate the cell of origin of human cancers, the behavior of cancer stem cells during therapy, and the evolution of resistance to anti-cancer drugs. We will use chronic myeloid leukemia (CML) treated with ABL tyrosine kinase inhibitors as a particular example and will validate the predictions of the mathematical models in a murine model of CML. Our approach will provide a validated quantitative understanding of cancer stem cells, and allow us to apply mathematical modeling of cancer stem cells to biologically and clinically important issues including response to targeted therapies and evolution of drug resistance.
The Specific Aims are 1. To design a mathematical framework of CML stem cells. 2. To validate the predictions derived in Aim 1 in a murine model of CML. 3. To study the dynamics of resistance to anti-cancer therapy. 4. To investigate the cell of origin of CML. The research program outlined in this proposal will establish a quantitative understanding of tumor stem cells in cancer initiation, progression, treatment, and resistance and will provide theoretical frameworks indispensable for the understanding of cancer stem cell biology and the optimum administration of therapies. We will also test our mathematical models in an in vivo system, in order to demonstrate the relevance of our mathematical models to an experimental model. Although outside the scope of this proposal, the ultimate goal of this research program is to use mathematical models to develop a general framework for evaluating the role of cancer stem cells in oncogenesis, and to develop specific therapies which target cancer stem cells for human malignancies.

Public Health Relevance

In this proposal, we suggest to use mathematical and experimental techniques to study the behavior of cancer stem cells during cancer initiation, anti-cancer therapy, and the emergence of resistance. Our approach will provide a validated quantitative understanding of cancer stem cells, and we will apply our mathematical models of cancer stem cell biology to biologically and clinically important issues including response to targeted therapies and evolution of drug resistance. This will allow us to develop a general framework for evaluating the role of cancer stem cells in oncogenesis, and to develop specific therapies which target cancer stem cells for human malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138234-06
Application #
8326199
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (O2))
Program Officer
Arya, Suresh
Project Start
2008-09-24
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$475,049
Indirect Cost
$101,465
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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